Project Summary/Abstract: This study will be the first demonstration of changes in connectivity following a direct ablative intervention in neurocircuitry. Interest in neurosurgery for psychiatric illness is increasing dramatically. Controlled trials of stereotactic ablation and deep brain stimulation (DBS) are underway. However, knowledge of behavioral and brain mechanisms underlying these therapies remains limited. This Mentored Patient-Oriented Career Development Award (K23) focuses on mechanisms of therapeutic change after thermocapsulotomy for intractable obsessive-compulsive disorder (OCD). The research focuses on a surgical procedure that has continued in use for decades for OCD, but whose mechanisms of action remain virtually unstudied: ventral capsulotomy. Twenty-four patients undergoing ventral capsulotomy for intractable OCD will be recruited from the longstanding psychiatric neurosurgery program at Butler Hospital. Twenty-four healthy control participants will also be recruited. Aim 1 uses probabilistic tractography-derived human neural models, informed by known macaque neuroanatomy from histological data, to delineate neuroanatomical nodes and pathways affected by ventral capsulotomy for severe OCD. This will generate regions of interest for Aim 2, and will allow for analysis of changes in structural (diffusion tensor imaging) connectivity pre- and post- ventral capsulotomy for OCD. Aim 2 will examine resting state and task-based (response inhibition) effective connectivity changes pre- and post-ventral capsulotomy for severe OCD. This study represents an unparalleled opportunity to test hypotheses of the relationship between connectivity and therapeutic improvement after a planned ablation. The applicant will obtain a virtually unique combination of skills, building on prior knowledge of neuropsychological tasks and morphometric MRI analysis. To achieve the goal of conducting independent research in this area, the K23 training plan will emphasize 1) an in-depth understanding of neuroanatomy and how it can be used to inform neuroimaging analysis; 2) analysis and application of DTI and MRI connectivity data; and 3) advancing the applicant's knowledge of mechanisms of therapeutic change after treatments for neuropsychiatric disorders. This career development award provides a rich set of collaborators, with leading researchers in this field, for both training and research. The Applicant proposes comprehensive training in neuroimaging, neuroanatomy, multivariate statistics, and responsible research conduct. She is seeking to be trained to fill a niche in an area (interventional neuroscience) that is greatly expanding. She will acquire advanced skills needed to lead independent research on behavioral and brain mechanisms of therapeutic change after neurosurgery and other neurocircuitry-based interventions for OCD and related disorders.